1. Field of the Invention
The invention relates to the treatment of animal bodies by means of ultrasound, and comprises a method and apparatus for creating intense acoustic pressures interior to selected portions of an animal body without the need for focusing the incident acoustic radiation.
2. Background Information
Ultrasonic energy, applied to a selected region within a body from an extracorporeal transducer, is often used as a therapy means. Examples include ultrasonic ablation of tissue as shown, e.g., in U.S. Pat. No. 4,858,613, xe2x80x9cLocalization and Therapy System for treatment of spatially oriented focal diseasexe2x80x9d, issued Aug. 22, 1989, to Fry et al.; fracture of kidney stones, as shown, e.g., in U.S. Pat. No. 4,539,989, xe2x80x9cInjury Free Coupling of Therapeutic Shock Wavesxe2x80x9d, issued Sep. 10, 1985 to Forssmann et al; heat therapy, as shown in, e.g., U.S. Pat. No. 4,586,512, xe2x80x9cDevice for Localized Heating of Biological Tissue, issued May 6, 1986 to Do-huu; and destruction of thrombi, as shown, e.g., U.S. Pat. No. 5,509,896 xe2x80x9cEnhancement of Sonothrombolysis with External Ultrasound, issued Apr. 23, 1996 to Carter et al. The mechanisms of action for these applications require acoustic intensity levels sufficient to cause significant heating or mechanical disruption or destruction of tissue preferably only within a localized region.
The acoustic intensities used for treatment in the localized region of the body range from 0.5 to 100""s of watts per cm2 at the internal treatment site, at frequencies in the 100 kHz-2 MHz range. Prolonged exposure to intense acoustic fields causes tissue destruction through heating or mechanical action. Thus, it is important that the acoustic field be controlled so that only the target tissue receives prolonged exposure. Ultrasonic energy that passes through intervening layers of energy-absorbing tissue, like the skull, in order to reach the area targeted for treatment can cause heating in those intervening layers. Bone absorbs ultrasound at least thirty times more readily than brain tissue; thus, to avoid undue skull heating, acoustic intensities at the skull must be kept low.
The acoustic field at the skull can be shaped by geometric focusing, using either physical or electronic lenses to avoid undue skull heating. FIG. 1 illustrates this type of system. Ultrasound transducer 100 contains a lens structure 110 that produces a concave shaped wave front 120 that converge along paths 130 to a point of intended focus 175 after transiting the skull 125. The acoustic intensity at the convergence point 175 is many times higher than it is at the penetration area 150 of skull 125.
Geometric focussing becomes impractical when low frequency ultrasound is used, because physically large, impractical transducers and lenses are required. In such cases, low frequency ultrasound, below 100 kHz, may be used in combination with a lytic agent such as tissue plasminogen activator (tPA); the low frequency ultrasound increases the thrombolytic rate of the tPA. See, e.g., Suchkova, V et al xe2x80x9cEnhancement of Fibrinolysis with 40 kHz Ultrasoundxe2x80x9d, Circulation: 1998, pp. 1030-1035. However, at this frequency, a geometrically focussed system requires transducers and lenses of 25 cm diameter or larger in order to provide a moderate degree of focussing. Such large transducers require liquid coupling media between the transducer/lens structure, and the subject tissue in order to efficiently couple acoustic waves into the tissue. Since bone is characterized by different sound velocities than either the coupling media or the target brain tissue, complex lenses that can correct for local variations in refractive index are used. Measurements of skull thickness and a map of refractive index over the entrance surface of the ultrasound are then required in order to compute the necessary shape of the lens. This leads to a complicated and large ultrasound system.
Another disadvantage of a lens based system is that there is no built in safety factor should the wrong lens or acoustic power levels be inadvertently used. Inertial cavitation, which arises in liquids in the presence of high acoustic intensity levels, is known to damage living tissue, and therefore should be avoided.
It is an therefore an object of this invention to provide an improved system that delivers the desired acoustic energy within a living being without employing cumbersome, large lenses with their unwieldy coupling components, while keeping the applied acoustic intensities at acceptably low levels at non target tissue sites.
It is further an object of this invention to provide a system that delivers the desired acoustic energy within a living being, but does not require a measurement of tissue thickness in order to do so.
Still a further an object of this invention is to provide a system that delivers the desired acoustic energy within a living being, but which does not require a measurement of refractive index in order to do so.
Yet another object of this invention is to provide a system that does not require that the shape of a lens, either physical or electronic, be varied in order to compensate for local refractive index variations within a living being.
Yet another object of this invention is to provide a system which includes a method to spatially position a region of therapeutic acoustic intensity within a desired region of a selected volume.
Yet another object of this invention is to provide a system which includes a method of placing a region of therapeutic acoustic intensity in a predetermined location within a selected volume.
We have observed that many body structures act as resonators. The brain vault, for example, is bounded by layers of differing acoustic impedance, thereby causing reflection of acoustic waves at these boundaries. At frequencies in the 0-500 kHz range, there is little attenuation of longitudinal acoustic waves in the brain or skull, and if reflection at a boundary layer is near total, then acoustic waves pass back and forth through tissue many times creating a trapped mode resonator.
FIG. 2 illustrates the acoustic field in such a resonator. Ultrasound transducer 200 emits wave fronts 250 that transit the skull 225. Due to low acoustic loss in the tissue 235 in the cranial vault, the waves travel to the other side of the skull, where they are reflected as wave 255 due to the differing acoustic impedance of the bone and air which forms the skull and its outside boundary. These reflected waves 255 again travel across the cranial vault and again are reflected by the bone and air interfaces, and return across the cranial vault. This process is repeated many times, and builds up to the point where the internal acoustic energy losses in the cranial vault and the reflections at the skull balance the acoustic energy applied by transducer 200. At points 280 where the acoustic waves intersect, pressure nodes and anti-nodes are formed, depending on whether the wave fronts interfere out of phase or in phase, respectively. A common measure of the resonant property of a system is its quality factor, defined as 2xcfx80 times the ratio of stored energy to the lost energy per cycle. In practice, we have measured Q""s of from 10 to more than 100 in isolated skull experiments, with node to anti-node pressure ratios of from 10 to more than 100.
We make use of this fact by treating a body part that is to be subjected to acoustic waves below 500 kHz, and preferably below 100 kHz, as a trapped mode resonator. Such a resonator can exhibit a high Q (e.g., a Q of 10 or more) at certain frequencies that cause wave front interference from multiple reflections to add up in phase. Examples of trapped mode resonators within a body include (a) the cranial vault bounded by air, bone and neck tissue; (b) arms; (c) legs; and (d) the thorax, all of which are bounded by air and other tissues. In high Q resonators, very high pressures can be achieved in the resonator cavity for very modest input power U. The differing impedance of skull and air from brain assures that there will be internal reflections, thereby causing the cranial vault to act as a resonator. At frequencies below 500 kHz, little acoustic power need be delivered to the skull to maintain the acoustic field in the brain, because there is little skull or brain heating caused by absorption or other losses
The amount of energy, W, stored in the resonator at a given frequency is a function of the frequency; thus to maximize the pressure field, the cavity must be xe2x80x9ctunedxe2x80x9d to a frequency which maximizes W. In accordance with a first embodiment of the invention, we vary the exciting frequency in accordance with the average pressure at the region of interest is found. Typically, we seek to maximize this pressure. The pressure field at the skull surface may be used as a proxy for the pressure field within the cranial vault, so that a surface transducer may be used to indirectly monitor the pressure within the region of interest and thus the stored energy, W. The surface pressure measurement may be made either by dedicating to this purpose one or more transducers attached to the resonator surface, or by momentarily turning off the electrical drive to one or more elements of exciting transducers and using them in a receive mode.
In accordance with a second embodiment of the invention, we maintain a high Q in the region of interest in the cavity by varying the driving frequency in accordance with the acoustic impedance of the cavity as seen by the driving transducer. Typically, we seek to maximize this impedance. The cavity impedance will be a local maximum at each frequency where the Q of the cavity reaches a local maximum. The cavity impedance can be calculated if the relationship between the electrical impedance of the transducer and the acoustic load impedance applied to the acoustic port of the driving transducer is known. Often a transducer can be treated as a three port network, containing two acoustic ports and one electrical port. In this case, the impedance of any port can be expressed in terms of the physical characteristics of the transducer, and the acoustic load impedance on each of the other two ports.
In accordance with a third embodiment of the invention, we excite the cavity with a short pressure pulse, h(t), via a broadband transducer placed in contact with the skull, e.g., a transducer that emits a pulse whose frequency components preferably lie primarily (as determined, e.g., by its 3-db points) within a range of from about 20 kHz to about 40 kHz. The Fourier transform of the pressure pulse h(t) is H(f) and it contains a multiplicity of frequency components. The acoustic response of the resonant cavity is recorded by monitoring the time response g(t) of the pressure at the surface of the skull, either with the same transducer acting as a receiver, or with another broadband transducer. The time pressure waveform, g(t), is then converted to its frequency domain equivalent
xe2x80x83G(f)=(g(t))
Those frequencies f1 . . . fn in G(f) where peaks in the amplitude response of G(f)/H(f) occur correspond to resonant frequencies of the cavity. By controlling the Q""s corresponding to these resonant frequencies, the positions of the maxima and minima of the waveforms at the respective frequencies may be controlled by the user to thereby control the energy in a given region. Specifically, they may be positioned at desired specific sites within the cavity to thereby intensify the acoustic pressure at those sites without the use of acoustic lenses or the like, and may readily be moved about within the cavity under control of the user simply be controlling one or more characteristics of the electrical signals driving the acoustic transducers.
The Q of a resonator varies proportionally to the reciprocal of the internal losses in the resonator. Internal losses may vary because of changes in the absorption of acoustic energy within the material that fills the resonator cavity, such as due to the onset of cavitation. Should cavitation occur, the Q of the cavity decreases due to energy absorption by the oscillating cavitation bubbles. Provided that the energy, U, supplied to the cavity by the acoustic driving source is substantially constant, the acoustic pressures within the cavity decrease as cavitation occurs, thereby retarding the cavitation process.
The Q of the resonator can be estimated by observing the build up time or decay time (ring-down time) of the pressure field within the resonator. Build up time is the time taken for the acoustic field to reach approximately 63% of it""s final value. The decay time is the time taken for the acoustic field to decay to approximately 1/e (approximately 37%) of its initial value. Therefore by exciting the resonator cavity (e.g., a patient""s skull) with one or more exciting transducers, and measuring the build up time or, after build up has completed, turning the exciting transducers off and measuring the decay time, Q can be estimated using the approximation:
Qxcx9c3.12f/xcex1
where
f is the desired frequency;
xcex1 is the reciprocal of either the buildup or decay time.
As acoustic waves within the resonator are being reflected back and forth within the cavity, pressure nodes and anti-nodes are found within the cavity which correspond to places where destructive and constructive interference of the acoustic waves occur. Further in accordance with the present invention, the location and magnitude of the nodes and anti-nodes are controlled by adjusting the magnitude and/or phase of the waves within the cavity, in addition to varying the frequency as earlier described. One or more of these parameters may be controllably varied in order to achieve a desired placement and intensity of pressure maxima and minima within a cavity.
At any point within the resonant cavity, the time function of pressure can be described as:
P(t)=xcexa3Piexp(xcfx89it+"PHgr"i))
Where
P(t)=the instantaneous pressure at time t;
Pi=the peak pressure of the ith pressure wave;
xcfx89i=the i-th pressure waveform frequency at a time t, in radians/sec;
"PHgr"i=the relative phase delay of the i-th pressure waveform at time t. Phase delay is a function of both the position of the transducer used to introduce the i-th pressure wave into the cavity, and also the phase of the driving signal for the transducer relative to an arbitrary reference;
xcexa3 represents the summation operation over all pressure waveforms at time t that exist at this point within the cavity.
If all pressure waveforms have the same frequency, xcfx89, the resultant waveform is a standing wave of that frequency, whose amplitude is the vector sum of all of the individual pressure waveforms. A vector sum that is a minimum corresponds to a pressure node and a maximum sum vector corresponds to an anti node. The location of these nodes and anti-nodes can be controlled, therefore, by controlling xcfx89i, "PHgr"i, or Pi for some or all of the pressure waveforms. If the relative phase, frequencies and pressure amplitudes of all of the component waveforms are constant in time, then the locations of the pressure nodes and anti-nodes within the cavity are fixed. If any of xcfx89i, "PHgr"i or Pi are not constant in time, the locations of the pressure nodes and anti anti-nodes move within the cavity over time. It should be noted that "PHgr"i can be varied either by varying the phase of a signal driving a transducer, or by moving the active transducer aperture. The active transducer aperture is that portion of the transducer which is radiating or receiving acoustic energy. The active aperture may be moved electronically, by exciting different portions of one or more transducers at different times.
Pressure nodes and anti-nodes can be placed in known positions within the resonator or moved about so that these nodes and anti-nodes remain in one part of the cavity only for a predetermined period. To place a set of nodes and anti-nodes at some predetermined location, any of Pi, "PHgr"i, and xcfx89i can be adjusted. A preferred method is to adjust xcfx89i to achieve a peak pressure response within the cavity, and then adjust "PHgr"i to place the set of nodes and anti-nodes as needed. Moving pressure nodes and anti-nodes in time has the advantage of retarding or suppressing local heating and /or cavitation.